Cocaine abuse is a major public and social health problem in the United States. It is estimated that 2.4 million individuals are addicted to cocaine and unable to quit. Although extensive research has revealed the biochemical basis of cocaine addiction, there are no approved pharmacotherapies to treat cocaine addiction. Recently, several studies have suggested that an anti-cocaine vaccine may be a promising approach to treat cocaine addiction, by generating anti-cocaine antibodies in cocaine abusers that would prevent the cocaine molecule from gaining access to the brain where it induces its euphoric effects. However, most strategies to generate an efficacious anti-cocaine vaccine have not successfully induced long-lasting high titer antibodies that are not only systemic in nature, but prevalent along mucosal tracts that are sites of cocaine administration. These deficiencies might be alleviated through the use of an effective mucosal adjuvant compound in the anti-cocaine vaccine. Recently, we found that small molecule MC activating compounds are potent mucosal adjuvants against a wide variety of vaccine antigens, and do not induce deleterious side effects common to many well-known adjuvant compounds. In these studies, we propose to develop an anti-cocaine vaccine formulation utilizing a novel class of mucosal adjuvants, MC activating compounds, capable of generating high titer, systemic and mucosal surface anti-cocaine antibodies. If successful, this vaccine may have potent clinical efficacy in the treatment of cocaine addiction, and may eventually allow for the development of other successful vaccines against small molecule addictive agents. PUBLIC HEALTH RELEVANCE: Novel treatments are needed to assist those that are addicted to drugs of abuse. Studies proposed in this application will develop and evaluate novel vaccines for their ability to induce antibody responses specific for cocaine. These anti-cocaine antibodies have the potential to bind cocaine within the body and reduce the biological activity of cocaine and therefore provide a treatment strategy for those that desire to stop using cocaine. The novelty of our proposal includes the use of novel cocaine antigen formulations, the use of novel vaccine adjuvants and the use of a needle-free, mucosal route of immunization.